1. Field of the Invention
The present invention relates to a series of new carbapenem compounds, to methods using these compounds and to compositions containing these compounds, and provides processes for preparing these compounds.
2. Background and Information
The penicillins form a well known class of antibiotics, which have found considerable use in human and animal therapy for many years. Chemically, the penicillins have in common a .beta.-lactam structure, commonly referred to as "penam", which may be represented by the following formula: ##STR4##
However, although the penicillins still form a valuable weapon in the pharmaceutical armory, the development of new, and often penicillin-resistant, strains of pathogenic bacteria has increasingly made it necessary to search for new types of antibiotic.
In recent years, great interest has been shown in compounds having a carbapenem structure, that is compounds having a carbon atom in place of the sulfur atom at the 1-position and having a double bond between the carbon atoms in the 2- and 3-positions of the basic penam structure. The carbapenem structure may be represented by the following formula: ##STR5##
These penam and carbapenem structures form the basis for the semi-systematic nomenclature of the penicillin derivatives in accordance with the recommendations of the International Union of Pure and Applied Chemistry (IUPAC), and this nomenclature is generally accepted by those skilled in the art throughout the world and is used herein. The numbering system employed herein is that illustrated on the above formula (B).
Of the known carbapenem derivatives, the best known is a compound called "thienamycin", whose semi-systematic name is 2-(2-aminoethylthio)-6-(1-hydroxyethyl)carbapen-2-em-3-carboxylic acid. Although thienamycin is known to have remarkably potent and broad antibacterial activity, its chemical stability in the human body is poor, which restricts its practical use. Various attempts have, therefore, been made to modify the chemical structure of thienamycin in order to improve its chemical stability whilst maintaining or improving its superior activity, but there is still a continuing need to develop further carbapenem antibiotics with improved properties.
The present invention provides a new group of carbapenem derivatives which possess superior absorption and metabolic stability (as evidenced by improved recovery rates in the urine), as well as a broad antibacterial spectrum and low toxicity. The invention also provides synthetic processes for the preparation of the new carbapenem derivatives, as well as pharmaceutical compositions comprising the said derivatives suitable for human and animal administration.
Of the prior art known to us, the following are believed to be the closest:
U.S. Pat. No. 4,640,799 and U.S. Pat. No. 4,665,170 disclose carbapenem compounds in which there is a group --S--A--N at the 2-position. "A" can be various groups, and N represents a quaternized nitrogen-containing heterocyclic group attached to A through its quaternary nitrogen atom. These compounds differ from those of the present invention in that, where the compounds of the present invention contain a quaternized nitrogen-containing heterocyclic group having a quaternary nitrogen atom, this is not attached to the rest of the molecule via the quaternary nitrogen atom, but is attached via a carbon atom of the heterocyclic group.
European patent Specification No. 126 587 discloses a series of carbapenem compounds having a pyrrolidinylthio group at the 2-position. These differ from the compounds of the present invention which are quaternary nitrogen compounds in that these prior art compounds are not quaternary nitrogen compounds and they differ from the non-quaternized compounds of the present invention in the nature of the substituents on the heterocyclic ring. Certain of the compounds disclosed in this prior art may have good activity, but they are believed to be less well absorbed in vivo than are the compounds of the present invention.